Peptide amino-alcohol derivatives containing a tetrasubstituted carbon atom, inhibiting renin and acid proteases, process for obtention and therapeutical use

ABSTRACT

The present invention relates to peptide amino-alcohol derivatives containing a tetra substituted carbon atom. Said peptides inhibit the renin and acid proteases. The invention also relates to the process for their obtention and to pharmaceutical compositions.

The present invention relates to new peptide derivatives which inhibit renin and, more generally, acid proteases. It also relates to a process for their preparation and their application in therapy.

In 1970, UMEZAWA isolated a pentapeptide from a culture of streptomyces; this pentapeptide was called pepstatin and its structure was subsequently established and corresponds to the formula:

    isovaleryl-L-valyl-L-valyl-statyl-L-alanyl-statin

in which the name "statin" denotes the uncommon amino acid (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid.

It has been shown that pepstatin inhibits acid proteases and is active especially against pepsin, cathepsin D and renin. In particular, renin, an enzyme originating from the kidney, is involved in the sequence angiotensinogen--angiotensin I--angiotensin II in the conversion of angiotensinogen to angiotensin.

As a powerful vasoconstrictor, angiotensin II plays a part in regulating the arterial pressure. The possibility of using pepstatin to combat arterial hypertension in man has been considered. However, since pepstatin acts on all acid proteases and has a low solubility in aqueous media and a low affinity for renin, its use in therapy has proved difficult. Pepstatin derivatives have been described in the scientific literature. For example, attempts have been made to solubilize pepstatin by lengthening the peptide chain (J. Cardiovasc. Pharmacol., 1980, 2, 687-698).

According to the present invention, it has been found possible to obtain very active products not by lengthening the peptide chain but by introducing hydrophilic residues onto various sites of a peptide analogous to pepstatin. This is all the more surprising because the prior art (U.S. Pat. No. 4470971 to Merck) teaches that the presence of hydrophilic substituents decreases the inhibitory activity towards renin.

The present invention relates to peptides having a high level of activity as inhibitors of renin and other acid proteases.

The following abbreviations will be used in the present description and in the claims:

Amino acids and protecting or activating groups

These abbreviations are consistent with those indicated by the Nomenclature Commission of IUPAC-IUB, Biochemistry Section. The most recent recommendations are reported in Eur. J. Biochem., 1984, 138, 5-7 and 9-37.

Amino Acids:

    ______________________________________                                         Abu           alpha-aminobutyric acid                                          Ala           alanine                                                          Asn           asparagine                                                       Asp           aspartic acid                                                    Cpg           cyclopentylglycine                                               Gln           glutamine                                                        Gly           glycine                                                          His           histidine                                                        Ile           isoleucine                                                       Leu           leucine                                                          Met           methionine                                                       Nle           norleucine                                                       Nva           norvaline                                                        Phe           phenylalanine                                                    Phg           phenylglycine                                                    Ser           serine                                                           Val           valine                                                           (tauMe)His    (tele-methyl)histidine                                                          ##STR1##                                                        (Pyr-3)Ala    (pyridin-3-yl)alanine                                                           ##STR2##                                                        (Benzimidazol-2-yl)Ala                                                                        ##STR3##                                                        ______________________________________                                    

These amino acids are in the L configuration.

    ______________________________________                                         Sta:      statin:4-amino-3-hydroxy-6-methylheptanoic                                     acid                                                                 AHPPA:    4-amino-3-hydroxy-5-phenylpentanoic acid                             ACHPA:    4-amino-5-cyclohexyl-3-hydroxypentanoic acid                         ______________________________________                                    

Unless indicated otherwise, Sta, AHPPA and ACHPA are in the 3S,4S configuration.

Protecting and activating groups:

    ______________________________________                                         Ac:          acetyl                                                            Boc:         tert.-butoxycarbonyl                                              (Boc).sub.2 O:                                                                              bis(tert.-butocxycarbonic) anhydride                              HONSu:       N--hydroxysuccinimide                                             OEt:         ethyl ester                                                       OMe:         methyl ester                                                      ONp:         p-nitrophenyl ester                                               ONSu:        N--hydroxysuccinimide ester                                       iVa:         isovaleryl                                                        Z:           benzyloxycarbonyl                                                 ______________________________________                                    

The following abbreviations will also be used:

    ______________________________________                                         AcOEt:    ethyl acetate                                                        AcOH:     acetic acid                                                          Bop:      benzyloxytrisdimethylaminophosphonium hexa-                                    fluorophosphate                                                      TLC:      thin layer chromatography                                            DCCI:     dicyclohexylcarbodiimide                                             DCHA:     dicyclohexylamine                                                    DCU:      dicyclohexylurea                                                     DIPEA:    diisopropylethylamine                                                DMF:      dimethylformamide                                                    DMSO:     dimethyl sulfoxide                                                   Ether:    ethyl ether                                                          HOBt:     1-hydroxybenzotriazole                                               MeOH:     methanol                                                             NEM:      N--ethylmorpholine                                                   NMM:      N--methylmorpholine                                                  RT:       room temperature                                                     TFA:      trifluoroacetic acid                                                 Reduced Sta:                                                                             4-amino-6-methylheptane-1,3-diol                                     ______________________________________                                    

The asymmetric carbons for which the configuration is determined are shown as C*.

The compounds according to the invention correspond to the following general formula: ##STR4## in which:

R₁ represents an acyl group chosen from the following groups: alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkoxycarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, in which the alkyl group is optionally substituted by a hydroxyl group, heterocyclylcarbonylalkylcarbonyl, heterocyclylalkenylcarbonyl and cycloalkylcarbonyl, or represents a (lower alkyl)sulfonyl group which is unsubstituted or substituted on the alkyl by a free amino group or an amino group carrying a protecting group, or by a phenyl, or represents a phenylsulfonyl group which is unsubstituted or substituted on the phenyl nucleus by a lower alkyl;

R₂ represents a lower alkyl group which is unsubstituted or substituted by a phenyl, naphthyl, cyclohexyl or pyridyl, or R₂ represents a phenyl, naphthyl, cyclohexyl or pyridyl radical;

R₃ represents hydrogen a lower alkenyl, a phenyl, a naphthyl, a cycloalkyl containing 3 to 6 carbon atoms, a 5-membered or 6-membered monocyclic heterocyclic group which is unsubstituted or substituted with a lower alkyl or trifluoromethyl, or alternatively a lower alkyl which is unsubstituted or substituted by a free amino group or an amino group carrying a protecting group, by a di(lower alkyl)amino group, by a free carboxyl or a carboxyl esterified with a lower alkyl or a benzyl, by a free carbamoyl or a carbamoyl substituted with one or two lower alkyls or with a phenyl, by a hydroxyl, lower alkoxy or benzyloxy group, by a pyridylmethoxy group, by a (lower alkyl)thio, (lower alkyl)sulfinyl or (lower alkyl)sulfonyl group, by a phenyl which is unsubstituted or substituted with a hydroxyl, by a naphthyl, by a cycloalkyl containing from 3 to 6 carbon atoms, by a 5-membered or 6-membered monocyclic heterocyclic group which is unsubstituted or substituted with a lower alkyl or a trifluoromethyl, or by a bicyclic heterocyclic group which is unsubstituted or substituted with a lower alkyl or a trifluoromethyl;

Q represents isopropyl, phenyl or cyclohexyl, respectively forming with the radical: ##STR5## the residue of the amino acid Sta, AHPPA or ACHPA;

X is either a direct bond or the residue of an amino acid such as Ala, Nva, Val, Leu, Nle, Ile, Phg, Abu or Cpg;

R₄ represents hydrogen or a lower alkyl which is unsubstituted or substituted by an indolyl, pyridyl, imidazolyl or phenyl radical; and

R₅ represents an aliphatic or cyclic hydrocarbon group of 3 to 20 carbon atoms which is unsubstituted or substituted by a phenyl, hydroxyphenyl or amino group, the said hydrocarbon group simultaneously containing at least one hydroxyl group and at least one carbon atom not having a C--H bond;

and also any pharmaceutically acceptable salts thereof with mineral or organic acids or alkali metals or alkaline earth metals.

The preferred products according to the present invention have the formula (I) above in which R⁵ represents:

(a) a group: ##STR6## in which:

p represents an integer between zero and 5,

q represents an integer between 0 and 5,

R₆ represents hydrogen or a lower alkyl, and

R₇ represents hydrogen, a hydroxyl group, an amine group, a carboxyl group, a pyridyl group or a phenyl group which is unsubstituted or substituted by a hydroxyl, with the proviso that if q=0, R₇ is different from hydrogen; or

(b) a group: ##STR7## in which:

p is as defined above,

R₈ represents a lower alkyl, and

R₉ represents a lower alkyl which is unsubstituted or substituted by a free amino group or an amino group carrying a protecting group, or

R₈ and R₉ together form a cycloalkyl of 3 to 8 carbon atoms with the carbon to which they are joined.

The compounds of the invention preferably contain from 1 to 3 hydroxyl groups in the radical R₅.

Particularly preferred products of the formula (I) above are those in which R₅ is a group chosen from: ##STR8##

In the present description, the term "alkyl" denotes saturated or unsaturated alphatic hydrocarbon radicals containing from 1 to 10 carbon atoms, the preferred alkyl groups being the lower alkyls as defined below.

The expressions "lower alkyl" and "lower alkenyl", as used here, denote saturated or unsaturated aliphatic hydrocarbon radicals containing up to 6 carbon atoms.

The expressions "lower alkoxy" and "(lower alkyl)thio" represent hydroxyl and thiol groups substituted by a lower alkyl group as defined above.

The expression "5-membered or 6-membered monocyclic heterocycle" includes pyrrolidine, imidazole, thiazole, thiophene, furan, pyrrole, triazole, oxazole, isoxazole, pyridine and thiadiazoles.

The expression "bicyclic heterocycle" includes benzimidazole, benzothiazole, benzoxazole, indole or their hydrogenated homologs.

The expression "protecting group" is understood as meaning a protecting group normally used in peptide chemistry, for example Boc, Z or iVa.

The expression "acyl group" used to define R₁ includes the residues of aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids. Preferred acyl groups are the residue of esterified carbonic acid, especially the groups Boc and Z, the residue of alkanoic acids containing from 2 to 6 carbon atoms, especially the group iVa, the residue of cyclohexylcarboxylic acid, the residue of phenylaliphatic acids, especially the phenylacetyl, 3-phenylpropionyl and dibenxylacetyl groups, the residue of arylcarboxylic acids, such as naphthoic acid, biphenylcarboxylic acid and benzoic acid which is unsubstituted or substituted on the phenyl nucleus, especially in the benzoyl group, the residue of a carboxylic acid in which the carboxyl is bonded to a 5-membered or 6-membered monocyclic heterocycle, especially the picolinoyl, nicotinoyl and isonicotinoyl groups, and the residue of alkanoic or alkenoic acids, such as acetic acid, propionic acid, butyric acid, valeric acid and their omega-hydroxy or omega-oxo derivatives substituted in the omega position by a 5-membered or 6-membered monocyclic heterocycle, as exemplified above.

More particularly, the present invention relates preferentially to the peptide amino alcohols of the formula I in which R₂, R₃, Q, R₄ and R₅ are as defined above and R₁ represents one of the following groups: ##STR9## NH₂ CH₂ CH₂ --SO₂ -- BocNHCH₂ CH₂ --SO₂ --

ZNHCH₂ CH₂ --SO--

A--SO₂ --, in which A is a lower alkyl

C₆ H₅ --(CH₂)_(a) --SO₂ --, in which a=0, 1 or 2

Particular preference is given to the peptide amino alcohols of the formula (I) in which R₂, R₃, Q, R₄ and R₅ are as defined above and R₁ represents a group chosen from:

isovaleryl,

4-(pyridin-2-yl)-4-oxobutyryl,

4-(pyridin-2-yl)-4-hydroxybutyryl,

3-(pyridin-3-yl)propionyl,

4-(pyridin-3-yl)butyryl,

nicotinoyl and

benzenesulfonyl.

Particular preference is also given to the compounds of the formula (I) in which R₁, R₂, R₄, R₅ and Q are as defined above and R₃ is such that the residue --NH--CH(R₃)--CO-- represents the residue (tauMe)His.

Another class of preferred compounds of the invention consists of the compounds of the formula (I) in which:

R₁ represents a group chosen from the following groups: isovaleryl, tert.-butoxycarbonyl, 3-(pyridin3-yl) propionyl, 4-(pyridin-3-yl)butyryl and nicotinoyl;

R₂ represents a benzyl;

R₃ represents n-butyl or a methyl substituted by a heterocyclic radical chosen from imidazol-4-yl, 1-methylimidazol-4-yl, 2-methylimidazol-4-yl, pyridin-3-yl and benzimidazol-2-yl;

R₄ is hydrogen;

X represents the residue of one of the amino acids Ile or Ala; and

Q and R₅ are as defined above.

The products according to the invention can be prepared by the methods normally used in peptide chemistry. Thus, according to another feature, the invention relates to a process for the preparation of the peptide amino-alcohol derivatives of the formula I above, wherein an amino alcohol of the formula: ##STR10## in which W is a protecting group or hydrogen and R₄ and R₅ are as defined above, and in which the hydroxyl groups are optionally protected, is treated with a lower alkyl ester of the amino acid of the formula: protected ##STR11## or H--X'--OH in which X' has the definition given above for X, but X' is other than a direct bond, and Q is as defined above, the peptide chain is then lengthened in a stepwise fashion by coupling with the next, appropriately protected amino acids or fragments, the various operations being carried out using either an activated ester of the amino acid or fragment to be coupled or the N-protected amino acid in the presence of DCCI, and the N-protecting groups being cleaved after each coupling, either by hydrogenolysis or by hydrolysis in a strong acid medium, and, if appropriate, the hydroxyl groups of the resulting amino alcohol are deprotected by acid hydrolysis and, if necessary, the product thus obtained is converted to one of its pharmaceutically acceptable salts.

If the amino acid to be introduced into the sequence has a reactive group in its side chain, the said group should be blocked by an appropriate protecting group, which is subsequently removed.

The protection of the N-terminal amino acid by the group R₁ is carried out by known methods, either before the residue: ##STR12## is coupled with the next amino acid, or after coupling.

If the compound (I) carries a substituent R₃ such that the corresponding residue is an unnatural amino acid, this unnatural amino acid is prepared by known methods. It is then coupled with the next amino acid by the usual method.

The amino alcohol part is prepared by coupling an appropriately chosen amino alcohol with the desired amino acid. If the chosen amino alcohol is not commercially available, it can be prepared by reduction of the corresponding amino acid ester.

Like pepstatin, the compounds of the present invention have a marked inhibitory action on acid proteases; in particular, they have a very strong inhibitory action on human plasma renin activity, which in general is considerably greater than that of the natural product: pepstatin.

The products according to the invention were studied for their therapeutic properties and especially their inhibitory action on enzymes. More particularly, the compounds were evaluated "in vitro" in terms of their inhibition of human plasma renin activity (PRA).

I-METHOD OF EVALUATION

The method of evaluation is based on that of GUYENE (J. Clin. Endocrinol. Metab., 1976, 43, 1301). The inhibition of PRA is evaluated from a human plasma pool rich in renin (15 to 20 mg of angiotensin I released per milliliter per hour), incubated for 60 minutes at 37° C., in a phosphate buffer at pH 7.4, in the presence of increasing concentrations of the product to be studied.

Human plasma contains the substrate angiotensinogen and the enzyme:renin. The angiotensin I released during the reaction is measured by radioimmunoassay: Plasma Renin Activity Kit from Travenol (nos. CA 533, 553). An inhibitor of the conversion enzyme, phenylmethylsulfonyl fluoride (PMSF), is added to the incubation medium. The total incubation volume is 555 microliters made up as follows:

420 microliters of human plasma

11 to 50 microliters of the product to be studied, at variable concentrations

119 to 80 microliters of phosphate buffer 5 microliters of PMSF.

A 1N solution of acetic acid in methanol (19/1 by volume) and a 1N solution of sodium hydroxide in methanol (2/1 by volume) are prepared. In a mixture of equal volumes of these 2 solutions, a 0.001M stock solution of the product to be studied is prepared. The subsequent dilutions are then made up in the phosphate buffer. The quantity of solvent present in a solution does not interfere with the results.

II-RESULTS

The results are expressed as the dose of compound, evaluated in mol, which causes a 50% inhibition (IC₅₀) of the human plasma renin activity (PRA) observed in the absence of inhibitor.

The results obtained with various products of the invention are given in the following Table 1, which shows the IC₅₀ values of each molecule in terms of their inhibition of human plasma renin activity at pH 7.4. From 5 to 10 doses were required in order to determine these IC₅₀ values. Pepstatin, used as the reference substance, is always tested in parallel in each experiment. The results are expressed as their logarithmic value (-log IC₅₀).

                  TABLE 1                                                          ______________________________________                                                      Inhibition of                                                                  human PRA                                                         log IC.sub.50                                                                  SR no.       pH 7.4                                                            ______________________________________                                         Pepstatin    4.92                                                              43 574       8.58                                                              43 576       8.40                                                              43 603       9.32                                                              43 686       8.22                                                              43 707       8.45                                                              43 721       8.11                                                              43 737       8.67                                                              43 763       7.11                                                              43 799       8.26                                                              43 808       (a)                                                               43 842       (a)                                                               43 845       (a)                                                               43 860       7.48                                                              43 925       (a)                                                               43 966       7.72                                                              43 972       (b) 7.88                                                          44 094       7.74                                                              44 125       7.44                                                              ______________________________________                                          (a) means that the inhibition of human PRA is about 90% when the               concentration of the product is 10.sup.-10 molar.                              (b) means that the inhibition of PRA was measured on baboon plasma.      

The particularly high inhibitory activity of the products according to the invention can be seen from this table.

The toxicity of the products according to the invention is compatible with their use in therapy.

It is therefore possible to consider using the products according to the invention in areas of therapy where the inhibition of renin-angiotensin enzyme systems is justified, especially arterial hypertension, gastroduodenal ulcers and inflammatory complaints.

Thus, according to another feature, the present invention relates to antihypertensive drugs in which the peptides of the formula (I) or their pharmaceutically acceptable salts are present as active principles.

The peptide amino alcohols of the present invention can be administered in therapy by intravenous, intramuscular or subcutaneous injection. They are used in a solvent such as physiological serum (isotonic saline solution) or in a buffer such as phosphate buffer; they can also be suspended in a pharmaceutically acceptable aqueous or non-aqueous diluent. Each dosage unit can contain from 1 to 1000 mg of active principle.

The non-limiting examples which follow are given in order to illustrate the present invention.

The pH of the solutions in an organic solvent is measured or checked using moist pH indicator paper.

The indicated melting points (m.p.) are taken from triturated solids; they are measured by the capillary tube method.

The specific rotations ([α]_(D)) are measured at 25° C.

To run the infrared (IR) spectra, the product is dissolved in CH₂ Cl₂ or mixed with KBr to form a disk.

Finally, the nuclear magnetic resonance (NMR) spectra are run at 250 MHz in DMSO solution with hexamethyldisiloxane as the internal standard.

The following abbreviations are used:

    ______________________________________                                         s:           singlet                                                           d:           doublet                                                           m:           multiplet or unresolved signals.                                  ______________________________________                                    

Also,

H ar denotes aromatic H

H im denotes H of the imidazole

H pyr denotes H of the pyridine

H (reduced Sta) denotes H of 4-amino-6-methylheptane-1,3-diol in the 3R,4S or 3S,4S configuration

approx. means approximately.

The chemical shifts (delta) are measured in ppm.

EXAMPLE 1: ##STR13##

(1°) Boc-Nle-Sta-OCH₃

A solution of Boc-Nle-ONSu (900 mg), HOBt (421 mg) and TFA-Sta-OCH₃ (0.9 equivalent), containing sufficient NMM to bring the pH of the solution to about 7, is reacted in a mixture of equal volumes of CH₂ Cl₂ and dioxane (16 ml). After 18 hours, the mixture is evaporated to dryness, water is added, extraction is carried out with ether and the organic phase is washed successively with a solution of KHSO₄, water, a solution of NaHCO₃ and then a saline solution. After drying (MgSO₄) and evaporation, an oil is isolated which is purified by chromatography on silica gel (eluent: pentane/ethyl acetate, 1/1 by volume). Yield 85%.

M.p.=79°-81° C. after trituration in a CH₂ Cl₂ / ether mixture.

[α]_(D) =-53.1 (c=1; MeOH).

    ______________________________________                                         NMR SPECTRUM                                                                   Delta    Appearance Protons    Assignment                                      ______________________________________                                         7.16     d, J = 9 Hz                                                                               1 H        NHCO                                            6.82     d, J = 8 Hz                                                                               1 H        NHCO.sub.2                                      5.0      d, J = 4 Hz                                                                               1 H        OH                                              3.88-3.67                                                                               m          3 H        CH (alpha) (Nle),                                                              C .sub.--HNH,C .sub.--HOH                       3.50     s          3 H        OCH.sub.3                                       2.39-2.07                                                                               m          2 H        CH.sub.2 CO (Sta)                               1.65-1.07                                                                               m          18 H       (CH.sub.3).sub.3 C, CH,                                                        CH.sub.2                                        0.84-0.71                                                                               m          9 H        CH.sub.3 (Nle and                                                              Sta)                                            ______________________________________                                    

(2°) Boc-Phe-Nle-Sta-OCH₃

The peptide Boc-Nle-Sta-OCH₃ (800 mg) is treated at 0° C. for 10 minutes in TFA (8 ml) and the excess solvent is then evaporated off at RT under vacuum in a Buchi Rotavapor. A solution of Boc-Phe-ONp (924 mg), HOBt (384 mg) and NMM (400 mg), prepared in CH₂ Cl₂ (15 ml), is added at 0° C. to the salt thus obtained and the pH of the reaction medium is then brought to about 7 by the addition of a further quantity of NMM. After 24 hours, the mixture is evaporated to dryness, water is added, extraction is carried out with AcOEt and the organic phase is washed with a solution of KHSO₄, several times with a solution of Na₂ CO₃ and with an aqueous saline solution and then dried (MgSO₄). After evaporation of the solvent and filtration on silica gel (eluent: pentane/ethyl acetate, 4/6 by volume), the expected compound is isolated in the form of a white powder. Yield 69%.

M.p.=126°-129° C. after recrystallization from a CH₂ Cl₂ /hexane mixture.

[α]_(D) =-37.2 (c=1; MeOH).

    ______________________________________                                         NMR SPECTRUM                                                                   Delta     Appearance Protons    Assignment                                     ______________________________________                                         7.83      d, J = 8 Hz                                                                               1 H        NHCO                                           7.49      d, J = 8 Hz                                                                               1 H        NHCO                                           7.27-7.04 m          5 H        C.sub.6 H.sub.5                                6.93      d, J = 8 Hz                                                                               1 H        NHCO.sub.2                                     4.98      d, J = 4 Hz                                                                               1 H        OH                                             4.29-4.14 m          1 H        CH (alpha)                                     4.14-4    m          1 H        CH (alpha)                                     3.88-3.70 m          2 H        CH--NH-- and                                                                   CHOH (Sta)                                     3.50      s          3 H        OCH.sub.3                                      2.95-2.56 m          2 H        CH.sub.2 C.sub.6 H.sub.5                       2.37-2.08 m          2 H        CH.sub.2 CO (Sta)                              1.67-1.10 m          18 H       (CH.sub.3).sub.3 C,                                                            CH.sub.2 (Nle), CH,                                                            CH.sub.2 (Sta)                                 0.86-0.70            9H         CH.sub.3                                       ______________________________________                                    

(3°) Boc-Phe-Nle-Sta-OH

The previous solid (750 mg) is hydrolyzed at RT with sodium hydroxide (1.3 equivalents) in a mixture of water (5 ml) and dioxane (10 ml) for 3 hours. The mixture is evaporated to dryness in a Buchi Rotavapor at RT, water is then added, the mixture is acidified with a solution of KHSO₄ and extracted with 3 volumes of AcOEt, and the extract is washed with an aqueous saline solution and dried (MgSO₄). After evaporation of the solvent, a solid is isolated (yield 95%) which is used as such for the subsequent reactions. NMR shows that the peak at 3.50 ppm has totally disappeared.

[α]_(D) =-37.0 (c=1; MeOH).

(4°) 2-(Boc-isoleucylamino)-2-methylpropane-1,3-diol ##STR14##

320 mg of 2-amino-2-methylpropane-1,3-diol are dissolved in 20 cm³ of a mixture of equal volumes of DMF and CH₂ Cl₂ ; 1 g of Boc-Ile-ONSu is added and the reaction is left to proceed for 18 hours at RT, with stirring; a further 320 mg of 2-amino-2-methylpropane-1,3-diol are added and the reaction is then left to proceed for 72 hours at RT, with stirring. The mixture is evaporated to dryness and the crude reaction product is chromatographed on silica, eluting with a chloroform/ AcOEt mixture, 1/9 by volume, to give 617 mg of the expected product.

M.p.=123°-126° C.

(5°) SR 43574

125 mg of the compound obtained above are treated at 0° C. in TFA for 15 minutes. After evaporation of the excess solvent and washing of the salt with ether, a solution of this salt in the minimum quantity of acetonitrile is added to a solution of 200 mg of the peptide Boc-Phe-Nle-Sta-OH in 10 ml of acetonitrile, the pH being kept at about 7-8 by the addition of the necessary quantity of NMM. 173 mg of Bop are then added and the reaction is left to proceed for 24 hours. After evaporation of the solvent, the crude reaction product is taken up with water and extracted with AcOEt. The extract is washed with a solution of NaHCO₃, a solution of KHSO₄ and a saline solution and dried, and the solvent is then evaporated off; after drying and evaporation of the solvent, the product is crystallized from an AcOEt/hexane mixture and then chromatographed on silica and recrystallized from a CH₂ Cl₂ /isopropyl ether mixture.

Weight=171 mg.

m.p.=107°-110° C.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta    Appearance  Protons    Assignment                                     ______________________________________                                          8.0-7.48                                                                               3 d,        3 H        NHCO                                                    J approx. 8 Hz                                                        7.06-7.30                                                                               m           6 H        C.sub.6 H.sub.5, NHCO                                                          (diol)                                         6.96     d, J approx.                                                                               1 H        NHCO.sub.2                                              8 Hz                                                                  4.86     d, J approx.                                                                               1 H        OH (Sta)                                                4 Hz                                                                  4.71     t, J approx.                                                                               2 H        OH (diol)                                               4 Hz                                                                  4.29-3.66                                                                               m           5 H        CH (alpha),                                                                    CH (OH)                                        3.50-3.25                                                                               m           4 H        (CH.sub.2).sub.2 --OH                          2.97-2.57                                                                               m           2 H        CH.sub.2 C.sub.6 H.sub.5                       2.20-2.00                                                                               m           2 H        CH.sub.2 CO                                    1.70-1.00                                                                               m           21 H       C(CH.sub.3).sub.3, CH.sub.2                                                    (Nle), CH, CH.sub.2                                                            (Sta and Ile)                                  1.08     s           3 H        CH.sub.3                                       0.91-0.68                                                                               m           15 H       CH.sub.3 (Nle, Sta,                                                            Ile)                                           ______________________________________                                    

EXAMPLE 2 ##STR15##

(1°) Boc-Nle-AHPPA-OCH₃

Boc-AHPPA-OCH₃ (3.0 g) is dissolved in TFA (20 ml) by the usual technique and the salt obtained is dissolved in CH₂ Cl₂ and then neutralized at 0° C. with NMM. Boc-Nle-ONSu (3.3 g) and HOBt (1.6 g) are subsequently added to the reaction medium, which is then stirred for 18 hours at RT, the pH of the solution being kept at about 7-8 by the addition of further quantities of NMM. After the usual treatments, the residue is chromatographed on silica gel (eluent: CH₂ Cl₂ / AcOEt, 1/1 by volume). The peptide crystallizes on evaporation of the solvent in a Buchi Rotavapor in the cold (yield 80%).

M.p.=89°-90° C.

IR (CH₂ Cl₂): 3420-1715-1675 cm⁻¹

[α]_(D) =-61.5 (c=1; MeOH).

(2°) Boc-Phe-Nle-AHPPA-Och₃

The previous compound (3.5 g) is dissolved at 0° C. in TFA (30 ml). The salt obtained by evaporation of the excess reactant by the usual method is dissolved in CH₂ Cl₂, neutralized at 0° C. with NMM and then added at 0° C. to a previously prepared solution of Boc-Phe-ONp (3.3 g), HOBt (1.33 g) and NMM (808 mg) in CH₂ Cl₂. The mixture is stirred for 18 hours at RT and the organic phase is then washed with water, a solution of Na₂ CO₃, a solution of KHSO₄ and water and subsequently dried (MgSO₄). On evaporation of the solvent, a solid is isolated which is triturated in ether and then filtered off; it is homogeneous in TLC. Yield 75%.

M.p.=182°-183° C.

[α]_(D) =-50.7 (c=1; MeOH).

    ______________________________________                                         NMR SPECTRUM                                                                   Delta    Appearance Protons    Assignment                                      ______________________________________                                         7.27-7.04                                                                               m          10 H       ar                                              5.23     d, J = 4 Hz                                                                               1 H        OH                                              4.27-3.80                                                                               m          4 H        CH (alpha) (Phe                                                                and Nle), CHNH                                                                 and CHOH                                        3.49     s          3 H        OCH.sub.3                                       1.61-1.00                                                                               m          15 H                                                       0.80     t, J = 6 Hz                                                                               3 H        CH.sub.3 (Nle)                                  ______________________________________                                    

(3°) Boc-Phe-Nle-AHPPA-OH

A solution of the ester described in the previous step (2 g) in dioxane (100 ml) is hydrolyzed at RT for 4 hours with a solution of sodium hydroxide (178 mg) in water (10 ml). Subsequent treatment according to Example 1, step 2, gives the acid, which is triturated in isopropyl ether, filtered off and dried in vacuo (yield 95%).

M.p.=161°-162° C.

(4°) 2-(Boc-isoleucylamino)-2-hydroxymethylpropane-1,3-diol ##STR16##

A suspension of tris(hydroxymethyl)aminomethane (1.32 g) in 40 ml of DMF is added to a solution of Boc-Ile-ONSu in DMF (10 ml). After stirring for 18 hours, the mixture is concentrated in vacuo, the concentrate is taken up with water, extraction is carried out with AcOEt and the extract is dried and concentrated. The concentrate is chromatographed on silica, eluting with an AcOEt/MeOH mixture, 9/1 by volume. The expected product is collected; it crystallizes from a CH₂ Cl₂ / isopropyl ether mixture.

Weight=247 mg.

m.p.=122°-124° C.

[α]_(D) =-24.0 (c=0.41; MeOH).

(5°) SR 43576

The Boc group is removed in the usual way, with TFA, from 218 mg of the compound obtained above. The solid obtained is taken up with CH₂ Cl₂, 4 ml of DMF are added, the solution is neutralized in the cold by the addition of a sufficient quantity of DIPEA, the peptide Boc-Phe-Nle-AHPPA-OH (369 mg) and Bop (287 mg) are then added and the mixture is stirred for 18 hours at RT, the pH being kept at about 7. The mixture is concentrated in vacuo (pressure: 5 mm Hg), the concentrate is taken up with CH₂ Cl₂ and the mixture is washed with water, a solution of Na₂ CO₃ and a solution of KHSO₄ and then dried and concentrated. The solid obtained is chromatographed on silica, eluting with a chloroform/ methanol mixture, 95/5 by volume. The expected product is recrystallized from a hexane/ether mixture.

Weight=265 mg.

m.p.=94°-95° C.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta   Appearance   Protons    Assignment                                     ______________________________________                                         7.96-7.65                                                                              m            3 H        NHCO                                           7.29-7.00                                                                              m            11 H       C.sub.6 H.sub.5 + NHCO                         6.95    d, J = 8 Hz  1 H        NHCO.sub.2                                     5.07    d, J approx. 4 Hz                                                                           1 H        OH.sup.2                                       4.63    t, J approx. 4 Hz                                                                           3 H        CH.sub.2 --OH                                  4.30-3.75                                                                              m            5 H        CH (alpha),                                                                    CHOH                                           3.57-3.38                                                                              m            6 H        (CH.sub.2).sub.3 OH                            2.95-2.50                                                                              m            4 H        CH.sub.2 C.sub.6 H.sub.5                       2.30-2.00                                                                              m            2 H        CH.sub.2 CO                                    1.68-0.93                                                                              m            18 H       C(CH.sub.3).sub.3, CH.sub.2                                                    (Nle), CH,                                                                     CH.sub.2 (Ile)                                 0.86-0.66                                                                              m            9 H        CH.sub.3 (Ile, Nle)                            ______________________________________                                    

EXAMPLE 3 ##STR17##

The Boc group is removed in the usual way, with TFA, from 240 mg of the SR 43576 prepared in the previous example. After evaporation of the excess solvent in vacuo, a residue is obtained which is taken up with CH₂ Cl₂, 5 ml of DMF are added, the mixture is neutralized in the cold by the addition of a sufficient quantity of DIPEA, and 68 mg of 3-(pyridin-3-yl)propionic acid and 84 mg of Bop are then added. The mixture is stirred for 18 hours at RT, the pH being kept at about 7 by the addition of DIPEA. It is concentrated in vacuo (pressure=5 mm Hg), the concentrate is taken up with AcOEt and the mixture is washed with an aqueous carbonate solution and water and then dried and concentrated. After chromatography on silica, eluting with a CHCl₃ /MeOH mixture, 9/1 by volume, the expected product is collected; it solidifies from a hexane/ ether mixture.

Weight=135 mg.

m.p.=90°-92° C.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta  Appearance   Protons  Assignment                                        ______________________________________                                         8.34-7.00                                                                             m            19 H     C.sub.5 H.sub.4 N, C.sub.6 H.sub.5,                                            NHCO                                              5.09   d, J approx. 4 Hz                                                                           1 H      OH (AHPPA)                                        4.64   t, J approx. 4 Hz                                                                           3 H      OH (triol)                                        4.57-3.70                                                                             m            5 H      CH (alpha) (Phe,                                                               Nle, Ile), CHOH                                                                and CHNH (AHPPA)                                  3.57-3.38                                                                             m            6 H      CH.sub.2 OH                                       2.96-2.50                                                                             m            6 H      CH.sub.2 --C.sub.5 H.sub.4 N,                                                  CH.sub.2 --C.sub.6 H.sub.5 (Phe),                                              CH.sub.2 --C.sub.6 H.sub.5 (AHPPA)                2.34-2.00                                                                             m            4 H      CH.sub.2 CO (AHPPA),                                                           C.sub.5 H.sub.4 NCH.sub.2 --CH.sub.2 CO           1.68-0.92                                                                             m            9 H      CH.sub.2 (Nle), CH                                                             and CH.sub.2 (Ile)                                0.86-0.66                                                                             m            9 H      CH.sub.3 (Nle, Ile)                               ______________________________________                                    

EXAMPLE 4 ##STR18##

(1°) 3-(Pyridin-3yl)propionyl-Phe-His-Sta-OCH₃

500 mg of Boc-Phe-His-Sta-OCH₃ are treated at 0° C. for 5 minutes with 5 ml of TFA; the mixture is evaporated to dryness and the salt is then precipitated in ether. The salt is taken up with 15 ml of acetonitrile, 132 mg of 3-(pyridin-3-yl)propionic acid and 385 mg of Bop are then added and the mixture is neutralized to about pH 7 by the addition of DIPEA. After 24 hours, it is evaporated to dryness, an aqueous carbonate solution is added and extraction is carried out with AcOEt. The organic phase is washed several times with a solution of Na₂ CO₃, water and then an aqueous saline solution, dried (MgSO₄) and then evaporated to dryness. The residue is dissolved in a 3M solution of KHSO₄ and the impurities are extracted with ether. The aqueous phase is neutralized with a solution of NaHCO₃. The precipitate is extracted with several volumes of AcOEt and the organic phase is washed with a solution of Na.sub. 2 CO₃ and an aqueous saline solution and then dried (MgSO₄) and evaporated. A white solid is isolated which is recrystallized from a methanol/isopropyl ether mixture.

Weight=97 mg;

m.p.=168°-170° C;

[α]_(D) =-30.6 (c=1; MeOH).

(2°) 2-(Boc-isoleucylamino)-2-methylpropane-1,3-diol

This compound is obtained in Example 1, step 4.

(3°) SR 43 737

76.5 mg of the compound obtained in step 1 are dissolved in 6 ml of a methanol/water mixture (5/1 by volume), 5 drops of 30% sodium hydroxide solution are added and the mixture is left in a refrigerator overnight. It is acidified to about pH 3 by the addition of a solution of KHSO₄ and evaporated to dryness. A suspension of the dry residue in 4 ml of DMF is added all at once, at 0° C., to 5 ml of CH₂ Cl₂ containing 61 mg of Bop and the TFA salt of 44 mg of the compound obtained in step 2. The mixture is neutralized by the addition of DIPEA and stirred for 24 hours. It is evaporated in vacuo at RT and an aqueous carbonate solution is then added. The precipitate is extracted with CH₂ Cl₂. The extract is washed several times with an aqueous saline solution. It is dried (MgSO₄) and the solvent is then evaporated off. The solid obtained is chromatographed on silica gel, eluting with methanol/ chloroform mixtures containing increasing proportions of methanol.

M.p.=108°-110° C.

    ______________________________________                                         NMR SPECTRUM                                                                    ##STR19##                                                                     Delta  Appearance Protons  Assignment                                          ______________________________________                                         11.5-10.0                                                                             broad s    1 H      NH imidazole                                                                   (H1)                                                8.39-8.27                                                                             m          3 H      H2, H6 (C.sub.5 H.sub.4 N), NHCO                    8.23   d, J = 8 Hz                                                                               1 H      NHCO                                                7.75   d, J = 8 Hz                                                                               1 H      NHCO                                                7.48   s          1 H      H2 (imidazole)                                      7.42   d, J approx.                                                                              1 H      H4 (C.sub.5 H.sub.4 N)                                     8 Hz                                                                    7.27   s          1 H                                                                                      ##STR20##                                          7.25-7.05                                                                             m          7 H      C.sub.6 H.sub.5, H5 (C.sub.5 H.sub.4 N), NHCO       6.79   s          1 H      H4 (imidazole)                                      5.06-4.60                                                                             m          3 H      OH                                                  4.50- 4.00                                                                            m          3 H      CH (alpha)                                          3.81-3.64                                                                             m          2 H      C .sub.--HNH and C .sub.--HOH                                                  (Sta)                                               3.50-3.00                                                                             m          4 H      CH.sub.2 OH and H.sub.2 O                           3.00-2.58                                                                             m          6 H      C .sub.--H.sub.2C.sub.6 H.sub.5,                                               C .sub.--H.sub.2imidazole,                                                     C .sub.--H.sub.2C.sub.5 H.sub.4 N                   2.40-2.29                                                                             m          2 H      CH.sub.2CO                                          2.19-1.95                                                                             m          2 H      CH.sub.2CO (Sta)                                    1.08   s          3 H                                                                                      ##STR21##                                          1.71-0.93                                                                             m          6 H      CH and CH.sub.2                                                                (Sta and Ile)                                       0.84-0.65                                                                             m          12 H     CH.sub.3 (Ile and Sta)                              ______________________________________                                    

EXAMPLE 5 ##STR22##

This compound is prepared from SR 43 574 (138 mg) by following the procedure of Example 3.

Weight=60 mg.

m.p.=86°-87° C.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta  Appearance   Protons  Assignment                                        ______________________________________                                         8.34-7.06                                                                             m            14 H     C.sub.5 H.sub.4 N, C.sub.6 H.sub.5, NHCO                                        ##STR23##                                        4.80   d, J approx. 4 Hz                                                                           1 H      OH (Sta)                                          4.69   t, J approx. 4 Hz                                                                           2 H      CH.sub.2O .sub.--H                                4.58-4.00                                                                             m            3 H      CH (alpha)                                                                     (Phe, Nle, Ile)                                   3.84-3.67                                                                             m            2 H      C .sub.--HOH and C .sub.--HNH                                                  (Sta)                                             3.50-3.25                                                                             m                     C .sub.--H.sub.2 OH and                                                        H.sub.2 O peak                                    3.0-2.55                                                                              m            4 H      C .sub.--H.sub.2 C.sub.6 H.sub.5,                                              C .sub.--H.sub.2 C.sub.5 H.sub.4 N                2.37-2.02                                                                             m            4 H      C.sub.5 H.sub.4 NCH.sub.2 C .sub.--H.sub.2                                     CO,                                                                            CH.sub.2 CO (Sta)                                 1.10   s            3 H                                                                                      ##STR24##                                        1.71-0.92                                                                             m            12 H     CH and CH.sub.2                                                                (Nle, Ile, Sta)                                   0.92-0.68                                                                             m            15 H     CH.sub.3 (Ile, Nle, Sta)                          ______________________________________                                    

EXAMPLE 6 ##STR25##

A solution of 0.534 g of 2-amino-2-methylpropanol in 5 ml of CH₂ Cl₂ is added to a solution of 1 g of Boc-Ile-ONSu in 10 ml of CH₂ Cl₂. After stirring for 20 minutes, the insoluble material is filtered off and the filtrate is then concentrated.

(2°) SR 43 686

The Boc group is removed, with 3 ml of TFA for 20 minutes at about 2° C., from 302 mg of the crude product obtained in the previous step. The residue is dissolved in 10 ml of CH₂ Cl₂, the solution is adjusted to pH by 7 by the addition of NMM, and 535 mg of Boc-Phe-Nle-Sta-OH and 442 mg of Bop are then added. After stirring for 48 hours, the mixture is washed with an aqueous saline solution, a solution of KHSO₄, a solution of NaHCO₃ and water and then dried and concentrated. The residue is chromatographed on silica, eluting with ethyl acetate. The expected product crystallizes in the cold from ether.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta  Appearance   Protons  Assignment                                        ______________________________________                                         6.91-7.90                                                                             m including 4 d                                                                             10 H     5 H ar, 5 NH                                             centered at                                                                    6.94-7.5-7.62-7.86,                                                            J = 8 Hz                                                                3.70-4.90                                                                             m including one d                                                                            7 H     OH (Sta),                                                centered at           OH (CH.sub.2 OH), 3 H                                    4.85, J = 4 Hz        (alpha) (Phe, Nle, Ile),                                                       2 H (Sta)                                         2.02-3.38                                                                             m             8 H     C .sub.--H.sub.2OH, C .sub.--H.sub.2C.sub.6                                    H.sub.5,                                                                        ##STR26##                                        0.69-2.69                                                                             m including 2 s                                                                             36 H     (CH.sub.2).sub.3 (Nle),                                  at 1.23 and 1.11      CH.sub.2CH (Sta), Boc,                                                          ##STR27##                                                                     CH.sub.3 (Nle, Sta, Ile)                          ______________________________________                                    

EXAMPLE 7 ##STR28##

(1°) Ethyl (R,S)-2-acetamido-2-ethoxycarbonyl-3-(pyridin-3-yl) propionate

48 g of diethyl acetamidomalonate are added to a solution of 11 g of sodium in 300 ml of EtOH, the mixture is then heated to the reflux temperature, 36 g of 3-chloromethylpyridine hydrochloride are added and reflux is maintained for 5 hours. EtOH is evaporated off, the residue is taken up with water, the mixture is extracted and the extract is dried, concentrated and chromatographed on silica. A CH₂ Cl₂ /AcOEt mixture, 60/40 by volume, elutes 23 g of the expected compound. (2°) (R,S)-(Pyr-3)Ala.2HCl

15 g of the previous diester are heated under reflux in 200 ml of 5 N HCl for 5 hours. The mixture is concentrated to dryness, EtOH is added and the mixture is evaporated. The process is repeated until the dihydrochloride recrystallizes: 15 g.

(3°) (R,S)-Boc-(Pyr-3)Ala

1 g of the previous dihydrochloride is dissolved in a mixture of equal volumes of water and dioxane. 350 mg of sodium hydroxide and 1 g of (Boc)₂ O are added and the mixture is then stirred overnight at RT. The dioxane is evaporated off, water is added, the mixture is neutralized with 8 g of Amberlite CG 120 L (acid form) and stirred for 1 hour at RT and the medium is then transferred to a column containing 8 g of the same resin. Elution is carried out with distilled water until the pH reaches 5 and then with a 4% solution of ammonia in distilled water. The eluates are concentrated. 0.69 g of the expected product is collected.

(4°) Boc-(Pyr-3)Ala-Sta-OMe

A mixture of 465 mg of Sta-OMe.TFA and 500 mg of Boc-(Pyr-3)Ala is stirred for 3days at RT in 10 ml of acetonitrile, in the presence of 780 mg of Bop, the medium being kept at about pH 7 by the addition of DIPEA. The mixture is then evaporated to dryness, water is added, extraction is carried out with AcOEt and the extract is washed with a solution of Na₂ CO₃, water and an aqueous saline solution and then dried over MgSO₄ and evaporated to dryness. The residue is chromatographed on silica gel with a CH₂ Cl₂ /AcOEt eluting mixture, 1/9 by volume, which successively elutes:

the less polar isomer A: 150 mg;

the more polar isomer B: 180 mg. ##STR29##

The more polar isomer obtained in the previous step (600 mg) is hydrolized in a methanol/dioxane/water mixture (10/10/10 v/v/v) and 70 mg of sodium hydroxide are added. After 25 minutes, the starting material has disappeared. The mixture is concentrated to dryness, the residue is taken up with dioxane, and a solution of hydrogen chloride in ethyl acetate is added to pH 4. The medium is concentrated again, the concentrate is solubilized in 25 ml of acetonitrile, and DIPEA is added to pH 7. 500 mg of 2-isoleucylamino-2-methylpropane-1,3-diol trifluoroacetate, previously neutralized in acetonitrile with DIPEA, are then added, followed by 650 mg of Bop, the pH is adjusted to between 8 and 9 and the mixture is then stirred overnight at room temperature. The medium is concentrated and the concentrate is taken up with an aqueous carbonate solution and then ethyl acetate; the organic phase is washed with potassium bisulfate solution and then dried and concentrated. The crude product is chromatographed on silica; an ethyl acetate/methanol mixture (95/5 v/v) elutes the product, which is crystallized from a methanol/ether mixture. 420 mg are collected.

(6°) SR 43 763

This step is carried out in the usual way, starting from 390 mg of the previous compound and 250 mg of Boc-Phe-ONp. After chromatography on silica, eluting with an ethyl acetate/methanol mixture (90/10 v/v), 325 mg of the expected product are obtained.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta  Appearance       Protons                                                                               Assignment                                      ______________________________________                                         8.48-7.05                                                                             m                13 H   H pyr, H ar, NHCO                               6.86   d, J = 8 Hz      1 H    NHCO.sub.2                                      4.91-4.65                                                                             m                3 H    OH (Sta), CH.sub.2 --OH                         4.65-3.92                                                                             m                3 H    CH (alpha) (Phe,                                                               Ile, (Pyr-3)Ala)                                3.83-3.67                                                                             m                2 H    CHOH, CHNH (Sta)                                3.50-3.13                                                                             m                --     CH.sub.2 --OH and H.sub.2 O                     3.10-2.50                                                                             m                4 H    CH.sub.2 C.sub.6 H.sub.5, CH.sub.2 C.sub.5                                     H.sub.4 N                                       2.16-1.90                                                                             m                2 H    CH.sub.2 CO (Sta)                               1.70-1.00                      CH.sub.2 and CH (Sta),                          1.22   s                18 H   CH.sub.2 and CH (Ile),                          1.09   s                       (CH.sub.3).sub.3 C, CH.sub.3                    0.90-0.64                                                                             m                12 H   CH.sub.3 (Sta),                                                                CH.sub.3 (Ile)                                  ______________________________________                                    

EXAMPLE 8 ##STR30##

(1°) 1-N-Boc-isoleucylamino-1-methoxycarbonylcyclohexane

A mixture of Boc-Ile-OH (3.81 g), 1-amino-1-methoxycarbonylcyclohexane (2.6 g) and Bop (7.29 g) in methylene chloride is stirred for 48 hours. The organic phase is washed with water, potassium bisulfate and sodium carbonate, dried and concentrated. The concentrate is chromatographed on silica, eluting with an ethyl acetate/methylene chloride mixture (50/50 v/v), and the expected product is collected; it crystallizes on evaporation of the solvent.

Weight=4.4 g.

m.p.=152°-155° C.

[α]_(D) ==39° (c=1; MeOH).

(2°) 1-N-Boc-isoleucylamino-1-hydroxymethylcyclohexane

303 mg of sodium aluminum hydride are added in small portions to a solution of the previous product (1.5 g) in ether and the mixture is stirred for 4 hours at RT. The reaction medium is poured into an iced solution of potassium bisulfate and the ether phase is decanted, dried and concentrated in vacuo to give a white solid, which is chromatographed on silica. An ethyl acetate/hexane mixture (50/50 v/v) elutes the expected product, which crystallizes on evaporation of the solvents.

Weight=1 g

m.p.=160°-162° C.

[α]_(D) =-28.2 (C=1; MeOH).

(3°) Sr 43799

This product is obtained by the usual coupling methods.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta   Appearance Protons   Assignment                                        ______________________________________                                         7.85    d, J = 8 Hz                                                                               1 H       NHCO                                              7.62    d, J = 8 Hz                                                                               1 H       NHCO                                              7.50    d, J = 8 Hz                                                                               1 H       NHCO                                              7.27-7.08                                                                              m          5 H       C.sub.6 H.sub.5                                   7.08    s          1 H       NHCO                                              6.93    d, J = 8 Hz                                                                               1 H       NHCO                                              4.85    d, J = 4 Hz                                                                               1 H       OH                                                4.53    t, J = 6 Hz                                                                               1 H       CH.sub.2 --OH                                     4.30-4.00                                                                              m          3 H       CH (alpha) (Phe,                                                               Nle, Ile)                                         3.86-3.68                                                                              m          2 H       CHNH, CHOH (Sta)                                  3.50-3.38                                                                              m          2 H       CH.sub.2 OH                                       2.96-2.55                                                                              m          2 H       CH.sub.2 C.sub.6 H.sub.5                          2.18-0.64                                                                              m          48 H      (CH.sub.3).sub.3, CH.sub.2 CO                                                  (Sta), CH, CH.sub.2,                                                           CH.sub.3 (Nle, Sta,                                                            Ile),                                                                          CH.sub.2 (cyclo-                                                               hexane)                                           ______________________________________                                    

EXAMPLE 9 ##STR31##

(1°) (tauMe)His-OMe.2HCl

(tauMe)His is prepared by the method described in J.R. Neth. Chem. Soc., 1978, 97 293-295. 4.5 g of the dihydrochloride of this product are dissolved in 50 ml of MeOH; the solution is saturated with HCl gas at 10°-15° C. and then stirred at RT for 72 hours. It is concentrated to dryness and the residue is taken up twice in ether and then in acetone, from which it crystallizes; 4 g are obtained after filtration.

(2°) Boc-Phe-(tauMe)His-OMe

508 mg of the previous product are placed in 25 ml of CH₂ Cl₂ and brought to pH 7 by the addition of DIPEA. 772 mg of Boc-Phe-ONp and 306 mg of HOBt are added. After stirring for 2 days at RT, the mixture is washed with iced water and then dried and concentrated. By chromatography on silica and elution with an AcOEt/MeOH mixture, 9/1 by volume, 849 mg of the expected product are collected.

(3°) Boc-Phe-(tauMe)His-ACHPA-OCH₃

800 mg of Boc-Phe-(tauMe)His-OMe are dissolved at 10° C. in 8 ml of a mixture of methanol and dioxane (166 vol/vol) and 90 mg of sodium hydroxide in 2 ml of water are then added. The temperature is kept at 10° C. for 1 hour and then at RT for 1 hour 30 minutes. The mixture is acidified to pH=3 with a solution of potassium bisulfate and then evaporated to dryness. The solid obtained is suspended in 20 ml of DMF at 0° C., in the presence of 820 mg of Bop, and the salt TFA.ACHPA-OCH₃ obtained from 620 mg of Boc-ACHPA-OCH₃, in 7 ml of DMF, is then added; finally, 500 mg of DIPEA are added. The pH is kept at 6-7 and the temperature is kept at between 0° C. and 10° C. for 2 hours, a further quantity of DIPEA is then added to bring the pH to 7 and the mixture is left to return to RT overnight. The solvent is evaporated off, an aqueous carbonate solution is added, extraction is carried out 3 times with ethyl acetate and the extracts are washed several times with an aqueous carbonate solution, water and an aqueous saline solution, dried and evaporated in vacuo. The solid is crystallized from a methanol/isopropyl ether mixture and then recrystallized in the cold from the minimum quantity of methanol to give 415 mg.

M.p.=164°-166° C.

[α]_(D) =-34.3 (c=0.61; MeOH). (4°) 3-(Pyridin-3-yl)propionyl-Phe-(tauMe)His-ACHPA-OCH₃

The trifluoroacetic acid salt of 364 mg of the product obtained in the previous step is prepared. This salt is placed in 10 ml of acetonitrile, 114 mg of 3-(pyridin-3-yl)propionic acid and 336 mg of Bop are added and the mixture is neutralized by the addition of DIPEA; the medium becomes homogeneous and a precipitate then appears. The solid is filtered off the next day and washed with water and ether (solid 1). Aqueous sodium carbonate is added to the filtrate, the acetonitrile is evaporated off and extraction is carried out with ethyl acetate. The insoluble material which appears in the organic phase is filtered off; the filtrate is dissolved in a solution of potassium bisulfate and then reprecipitated by the addition of sodium bicarbonate (solid 2). The solids 1 and 2 are identical and correspond to the expected product.

Weight=215 mg.

m.p.=211°-215° C.

[α]_(D) =-36.7 (c=0.27; MeOH).

(5°) SR 43842

The compound obtained above (206 mg) is acidified in the following manner. It is suspended in a mixture of water (4 ml) and methanol (10 ml), after which 5 drops of 30% sodium hydroxide solution, 4 ml of DMF and a further 5 drops of 30% sodium hydroxide solution are added. After stirring for 2 hours, it is seen that an almost complete solution has been formed. The insoluble material is filtered off, the methanol is evaporated off and the mixture is acidified to about pH 4-5 with a solution of potassium bisulfate and evaporated to dryness. The residue is treated at 0° C. with 2 ml of TFA and 86 of ##STR32## after evaporation, the residue is dissolved in 3 ml of DMF and neutralized with DIPEA. The TFA salt formed, the previous acid and 124 mg of Bop are mixed in 5 ml of DMF; the mixture is cooled to 0° C., DIPEA is added in a sufficient quantity to bring the pH to about 7-8 and the mixture is left to return to RT. After 3 days, the DMF is evaporated off, an aqueous carbonate solution is added and extraction is carried out with 3 volumes of an aqueous carbonate solution, water and an aqueous saline solution. After evaporation, a white solid is obtained (75 mg) which recrystallizes from an MeOH/ AcOEt mixture (27 mg).

M.p.=119°-124° C.

The mother liquor from crystallization is chromatographed on silica.

    ______________________________________                                         NMR SPECTRUM                                                                   Delta  Appearance Protons  Assignment                                          ______________________________________                                         8.40-8.24                                                                             m          3 H      2 H ortho pyr,                                                                 1 NHCO                                              8.17   d, J = 8 Hz                                                                               1 H      NHCO                                                7.71   d, J = 8 Hz                                                                               1 H      NHCO                                                7.45-7.07                                                                             m          10 H     1 H (tauMe),                                                                   2 H pyr, 5 H ar,                                                                ##STR33##                                          6.82   s          1 H      1 H (tauMe)His                                      4.92   broad s    1 H      O .sub.--H (ACHPA)                                  4.71   t, (J approx.                                                                             2 H      CH.sub.2O .sub.--H                                         4 Hz)                                                                   4.50-3.62                                                                             m          5 H      CH (alpha) (Phe,                                                               (tauMe)His, Ile),                                                              C .sub.--HNH, C .sub.--HOH (ACHPA)                  3.50   s          3 H      CH.sub.3 (tauMe)His                                 3.50-3.07                                                                             m          4 H      C .sub.--H.sub.2 OH (H.sub.2 O)                     3.07-2.58                                                                             m          6 H      CH.sub.2C.sub.5 H.sub.4 N,                                                     C .sub.-- H.sub.2C.sub.6 H.sub.5,                                              CH.sub.2imidazole                                   2.43-2.27                                                                             m          2 H      CH.sub.2COPhe                                       2.12-2.00                                                                             m          2 H      CH.sub.2 CO (ACHPA)                                 1.75-0.91                                                                             m          16 H     CH, CH.sub.2 (ACHPA, Ile)                           1.08   s                   CH.sub.3 (diol)                                     0.91-0.56                                                                             m          6 H      CH.sub.3 (Ile)                                      ______________________________________                                    

The following compounds (Table 2) were prepared by using the same methods. They are characterized by their NMR spectra.

                                      TABLE 2                                      __________________________________________________________________________     SR 43 721                                                                       ##STR34##                                                                     SR 43 808                                                                       ##STR35##                                                                     SR 43 845                                                                       ##STR36##                                                                     SR 43 860                                                                       ##STR37##                                                                     SR 43 925                                                                       ##STR38##                                                                     SR 43 966                                                                       ##STR39##                                                                     SR 43 972                                                                       ##STR40##                                                                     SR 44 094                                                                       ##STR41##                                                                     SR 44 125                                                                       ##STR42##                                                                     SR 44 177                                                                       ##STR43##                                                                     SR 43 721                                                                      Delta Appearance                                                                               Protons  Assignment                                            __________________________________________________________________________     7.91  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.67  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.48  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.27-7.07                                                                            m         6  H                                                                                     ##STR44##                                            6.95  d, J = 8 Hz                                                                              1  H     NHCO.sub.2                                            4.85  d, J approx. 4 Hz                                                                        1  H     OH (ACHPA)                                            4.68  t, J approx. 4 Hz                                                                        2  H     CH.sub.2O --H                                         4.31-4.0                                                                             m         3  H     CH (alpha) (Phe,                                                               Nle, Ile)                                             3.90-3.68                                                                            m         2  H     C --HOH and                                                                    C --HNH (ACHPA)                                       3.50-3.19                                                                            m                  C  --H.sub.2 OH and H.sub.2 O                                                  peak                                                  2.98-2.57                                                                            m         2  H     CH.sub.2 C.sub.6 H.sub.5                              2.23-2.00                                                                            m         2  H     C --H.sub.2CO (ACHPA)                                 1.23  s                  C(CH.sub.3).sub.3                                     1.08  s                                                                                                  ##STR45##                                            1.77  m                  CH and CH.sub.2 (Nle                                                  31 H     and Ile),                                                                      CH and CH.sub.2                                                                (ACHPA),                                              0.66  m                  CH.sub.3 (Nle and Ile)                                SR 43 808                                                                       7.1-8.32                                                                            complex m 14 H     5 NHCO, 5 H ar,                                             including 4 d      4 H pyr                                                     centered at                                                                    7.33, 7.42, 8.07,                                                              J = 6 Hz                                                                 3.24-4.83                                                                            complex m 12 H     OH (ACHPA),                                                 including 1 d      2 OH (diol),                                                centered at 4.83,  H (alpha) (Phe,                                             J = 6 Hz           Nle, Ala), CHOH                                                                and C --HNH                                                                    (ACHPA), 2 CH.sub.2OH                                 2.04-3                                                                               complex m 8  H     C --H.sub.2C.sub.6 H.sub.5, C --H.sub.2                     including 2 t      pyr, 2 C --H.sub.2CO                                        centered at 2.13                                                               and 2.63                                                                 0.49-1.75                                                                            complex m 27 H     9 CH.sub.2 (Nle,                                            including 1 s      ACHPA), 1 CH.sub.3                                          at 1.07 and 1 s    (Ala), 1 CH.sub.3                                           at 0.81            (diol), 1 CH.sub.3                                                             (Nle)                                                 SR 43 845                                                                      8.40-8.78                                                                            m         3  H     2 H ortho pyr,                                                                 1 NHCO                                                8.22  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.66  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.48  s         1  H     CH im                                                 7.42  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.26  s         1  H                                                                                     ##STR46##                                            7.23-7.07                                                                            m         7  H     5 H ar, 2 H pyr                                       6.78  broad s   1  H     CH im                                                 4.92  broad s   1  H     OH (ACHPA)                                            4.71  t, J approx. 4 Hz                                                                        2  H     CH.sub.2O --H                                         4.50-3.62                                                                            m         5  H     CH (alpha) (Phe,                                                               His, Ile), CHOH                                                                and C --HNH (ACHPA)                                   3.50-3.07                                                                            m         4  H     C --H.sub.2 OH (H.sub.2 O)                            3.07-2.58                                                                            m         6  H     C --H.sub.2C.sub.5 H.sub.4 N,                                                  C --H.sub.2C.sub.6 H.sub.5,                                                    C --H.sub.2imidazole                                  2.43-2.27                                                                            m         2  H     CH.sub.2COPhe                                         2.12-2.00                                                                            m         2  H     CH.sub.2CO (ACHPA)                                    1.75-0.91                                                                            m         16 H     CH and CH.sub.2 (Ile,                                                          ACHPA)                                                1.08  s         3  H     CH.sub.3 (diol)                                       0.91-0.56                                                                            m         6  H     CH.sub.3 (Ile)                                        SR 43 860                                                                      7.90-6.86                                                                            m         10 H     5 H ar, NHCO.sub.2,                                                             ##STR47##                                            4.82  d, J = 4 Hz                                                                              1  H     OH                                                    4.66  m         2  H     OH                                                    4.29-3.68                                                                            m         5  H     CH (alpha) (Phe,                                                               Nle, Ala), C --HNH                                                             and C --HOH (Sta)                                     3.50-3.25                                                                            m                  C --H.sub.2 OH and H.sub.2 O                          2.97-2.56                                                                            m         2  H     CH.sub.2 (Phe)                                        2.14-2.0                                                                             m         2  H     CH.sub.2 CO (Sta)                                     1.68-1.0                                                                             m         24 H     CH.sub.2 (Nle), CH                                                             and CH.sub.2 (Sta),                                                            CH.sub.3 at 1.08,                                                              (CH.sub.3).sub.3 C at 1.25                            0.89-0.71                                                                            m         9  H     CH.sub.3 (Nle and                                                              Sta)                                                  SR 43 966                                                                      8.42-8.18                                                                            m         4  H     2 H ortho pyr,                                                                 NHCO (His and Phe)                                    7.65  d, J = 8 Hz                                                                              1  H     NHCO (Ile)                                            7.46-7.04                                                                            m         10 H     2 H pyr, H im,                                                                 5 H ar, NHCO (Sta),                                                             ##STR48##                                            6.81  s         1  H     H im                                                  4.97-4.70                                                                            m         2  H     OH (Sta), CH.sub.2O --H                               4.50-4.30                                                                            m         2  H     CH (alpha) (Phe,                                                               His)                                                  4.05  t, J approx. 8 Hz                                                                        1  H     CH (alpha) (Ile)                                      3.77-3.61                                                                            m         2  H     C --HNH and C --HOH (Sta)                             3.43-3.19                                                                            m                  CH.sub.2 OH and H.sub.2 O                             3.50  s         3  H     NCH.sub.3                                             3.02-2.57                                                                            m         6  H     CH.sub.2 (Phe, His,                                                            C.sub.5 H.sub.4 N)                                    2.41-2.27                                                                            m         2  H     C --H.sub.2 CO                                        2.14-1.97                                                                            m         2  H     CH.sub.2 CO (Sta)                                     1.70-0.90                                                                            m         12 H     CH and CH.sub.2 (Ile),                                                         CH and CH.sub.3 (Sta),                                                          ##STR49##                                            0.90-0.61                                                                            m         12 H     CH.sub.3 (Ile)                                                                 CH.sub.3 (Ala)                                        SR 43 972                                                                       11.80                                                                               broad s   1  H     5 NH im                                               8.44-8.17                                                                            m         4  H     2 H ortho pyr,                                                                 2 H NHCO                                              7.70  d, J = 8 Hz                                                                              1  H     NHCO                                                  7.50-7.03                                                                            m         10 H     2 NHCO + H im,                                                                 5 H ar, 2 H pyr                                       6.79  s         1  H     H im                                                  4.95-3.62                                                                            m         8  H     3 OH, CH (alpha)                                                               (Phe, His, Ile),                                                               C --HNH and C --HOH                                                            (Sta)                                                 3.50-3.14                                                                            m                  CH.sub.2 OH (and H.sub.2 O)                           3.06-1.91                                                                            m         10 H     CH.sub.2 (His, Phe),                                                           CH.sub.2 (C.sub.5 H.sub.4 N),                                                  CH.sub.2 CO (Sta),                                                             CH.sub.2C --H.sub.2CO                                 1.71-0.91                                                                            m         8  H     CH and CH.sub.2 (Sta                                                           and Ile),                                                                      CH.sub.2C --H.sub.2CH.sub.2CO                         1.08  s         3  H     CH.sub.3                                              0.91-0.55                                                                            m         12 H     CH.sub. 3 (Ile and Sta)                               SR 44 094                                                                      7.90-6.87                                                                            m         10 H     5 H ar, 1 NHCO.sub.2,                                                           ##STR50##                                            4.83  d, J = 4 Hz                                                                              1  H     OH                                                    4.62  m         3  H     OH                                                    4.31-3.41                                                                            m         11 H     CH (alpha) (Phe,                                                               Nle, Ile), CH                                                                  and CHOH (Sta),                                                                C --H.sub.2 OH                                        2.98-2.57                                                                            m         2  H     C --H.sub.2 C.sub.6 H.sub.5                           2.29-2.00                                                                            m         2  H     CH.sub.2 CO (Sta)                                     1.70-0.63                                                                            m         other    aliphatic CH,                                                                  CH.sub.2 and CH.sub.3                                 SR 44 125                                                                      12.2  broad s   1  H     NH (benzimidazole)                                    8.48-6.96                                                                            m         14 H     5 H ar, C.sub.6 H.sub.4                                                        (benzimidazole),                                                               NHCO.sub.2, NHCO,                                                               ##STR51##                                            5.26  d, J = 5 Hz                                                                              1  H     OH (ACHPA)                                            4.78-4.61                                                                            m         3  H     CH.sub.2OH, CH (alpha)                                                         (benzimidazole)                                       4.23-3.67                                                                            m         4  H     CH (alpha) (Phe,                                                               Ile), C --HNH and                                                              C --HOH (ACHPA)                                       3.50-2.59                                                                            m                  CH.sub.2 OH, CH.sub.2 (Phe),                                                   CH.sub.2                                                                       (benzimidazole)                                       2.27-2.08                                                                            m         2  H     CH.sub.2 CO (ACHPA)                                   1.75-0.55                                                                            m         34 H     CH and CH.sub.2                                                                (ACHPA), CH, CH.sub.2,                                                         CH.sub.3 (Ile),                                                                C(CH.sub.3).sub.3, CH.sub.3                           SR 44 177                                                                      11.81 broad s   1  H     NH (imidazole)                                        8.42-7.05                                                                            m         13 H                                                                                     ##STR52##                                                                     4 H pyr, H im,                                                                 5 H ar                                                6.80  broad s   1  H     CH im                                                  5.0-5.49                                                                            broad m   2  H     OH                                                     4.5-4.34                                                                            m         2  H     CH (alpha) (Phe                                                                and His)                                              4.05  t, J = 8 Hz                                                                              1  H     CH (alpha) (Ile)                                      3.82-3.65                                                                            m         2  H     C --HNH and                                                                    C --HOH (ACHPA)                                       3.40-3.20                                                                            m         2  H     C --H.sub.2 OH (H.sub.2 O)                            3.05-2.27                                                                            m         8  H     C --H.sub.2C.sub.6 H.sub.5,                                                    C --H.sub.2imidazole,                                                          C --H.sub.2pyridine,                                                           C --H.sub.2 CO (Phe)                                  2.17-1.97                                                                            m         2  H     CH.sub.2 CO (ACHPA)                                   1.74-0.94                                                                            m         22 H     CH and CH.sub.2                                                                (ACHPA,                                                                        Ile), CH.sub.3                                        0.91-0.55                                                                            m         6  H     CH.sub.3 (Ile)                                        __________________________________________________________________________      [α].sub.D = -35.5° (c = 0.21; methanol);                          m.p. = 132-137° C. (after solidification in hexene).                    M.P. = 125-128° C. (triturated in ether);                               [α].sub.D = -32.3° (c = 0.6; methanol).                      

What is claimed is:
 1. A peptide amino-alcohol derivative of the formula: ##STR53## in which: R₁ represents an acyl group chosen from the following groups: alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkoxycarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, in which the alkyl group is optionally substituted by a hydroxyl group, heterocyclylcarbonylalkylcarbonyl, heterocyclylalkenylcarbonyl and cycloalkylcarbonyl, or represents a (lower alkyl)sulfonyl group which is unsubstituted or substituted on the alkyl by a free amino group or an amino group carrying a protecting group, or by a phenyl, or represents a phenylsulfonyl group which is unsubstituted or substituted on the phenyl nucleus by a lower alkyl;R₂ represents a lower alkyl group which is unsubstituted or substituted by a phenyl, naphthyl, cyclohexyl or pyridyl, or R₂ represents a phenyl, naphthyl, cyclohexyl or pyridyl radical; R₃ represents hydrogen, a lower alkenyl, a phenyl, a naphthyl, a cycloalkyl containing 3 to 6 carbon atoms, a 5-membered or 6-membered monocyclic heterocyclic group which is unsubstituted or substituted with a lower alkyl or trifluoromethyl, or alternatively a lower alkyl which is unsubstituted or substituted by a free amino group or an amino group carrying a protecting group, by a di(lower alkyl)amino group, by a free carboxyl or a carboxyl esterified with a lower alkyl or a benzyl, by a free carbamoyl or a carbamoyl substituted with one or two lower alkyls or with a phenyl, by a hydroxyl, lower alkoxy or benzyloxy group, by a pyridylmethoxy group, by a (lower alkyl)thio, (lower alkyl)sulfinyl or (lower alkyl)sulfonyl group, by a phenyl which is unsubstituted or substituted with a hydroxyl, by a naphthyl, by a cycloalkyl containing from 3 to 6 carbon atoms, by a 5-membered or 6-membered monocyclic heterocyclic group which is unsubstituted or substituted with a lower alkyl or a trifluoromethyl, or by a bicyclic heterocyclic group which is unsubstituted or substituted with a lower alkyl or a trifluoromethyl; R₄ represents hydrogen or a lower alkyl which is unsubstituted or substituted by an indolyl, pyridyl, imidazolyl or phenyl radical; R₅ represents an aliphatic or cyclic hydrocarbon group of 3 to 20 carbon atoms which is unsubstituted or substituted by a phenyl, hydroxyphenyl or amino group, the said hydrocarbon group containing at least one hydroxyl group and at least one carbon atom not having a C--H bond; Q represents isopropyl, phenyl or cyclohexyl, respectively forming with the radical: ##STR54## the residue of the amino acid Sta, AHPPA or ACHPA; and X is either a direct bond or the residue of an amino acid such as Ala, Nva, Val, Leu, Nle, Ile, Phg, Abu or Cpg;and also any pharmaceutically acceptable salts of the said peptide amino alcohol with mineral or organic acids or with alkali metals or alkaline earth metals.
 2. A peptide amino-alcohol derivative as claimed in claim 1 of the formula: ##STR55## in which R₁, R₂, R₃, Q, X and R₄ are as defined in claim 1, p represents an integer between zero and five,q represents an integer between 0 and five, R₆ represents hydrogen or a lower alkyl, and R₇ represents hydrogen, or a hydroxyl group, an amino group, a carboxyl group, a pyridyl group or a phenyl group which is unsubstituted or substituted by a hydroxyl, with the proviso that if Q=0, R₇ is different from hydrogen.
 3. A peptide amino-alcohol derivative as claimed in claim 1, of the formula: ##STR56## in which R₁, R₂, R₃, Q, X and R₄ are as defined in claim 1,p represents an integer between zero and 5, R₈ represents a lower alkyl, and R₉ represents a lower alkyl which is unsubstituted or substituted by a free amino group or an amino group carrying a protecting group, or R₈ and R₉ together form a cycloalkyl of 3 to 8 carbon atoms with the carbon atom to which they are joined.
 4. A peptide amino-alcohol derivative as claimed in claim 1, wherein R₁ represents one of the following groups: ##STR57## NH₂ CH₂ CH₂ --SO₂ -- BocNHCH₂ CH₂ --SO₂ --ZNHCH₂ CH₂ --SO₂ -- A--SO₂ --, in which A is a lower alkyl C₆ H₅ --(CH₂)_(a) --SO₂ --, in which a=0, 1 or 2or one of any salts of the said peptide amino alcohols with pharmaceutically acceptable mineral or organic acids.
 5. A peptide amino-alcohol derivative as claimed in claim 1, wherein R₁ represents a group chosen from the following groups:isovaleryl, 4-(pyridin-2-yl)-4-oxobutyryl, 4-(pyridin-2-yl)-4-hydroxybutyryl, 3-(pyridin-3-yl)propionyl, 4-(pyridin-3-yl)butyryl, nicotinoyl and benzenesulfonyl.
 6. A peptide amino-alcohol derivative as claimed in claim 1, wherein R₅ contains from 1 to 3 hydroxyl groups.
 7. A peptide amino-alcohol derivative as claimed in claim 1, wherein R₃ is such that the residue --NH--CH(R₃)--CO-- represents the residue (tauMe)His.
 8. A peptide amino-alcohol derivative of the formula: ##STR58## in which: R₁ represents a group chosen from the following groups: isovaleryl, tert.-butoxycarbonyl, 3-(pyridin-3-yl)propionyl, 4-(pyridin-3-yl)butyryl and nicotinoyl;R₂ represents a benzyl; R₃ represents n-butyl or a methyl substituted by a heterocyclic radical chosen from imidazol-4-yl, 1-methylimidazol-4-yl, 2-methylimidazol-4-yl, pyridin-3yl and benzimidazol-2-yl; R₄ is hydrogen; Q represents isopropyl, phenyl or cyclohexyl, respectively forming with the radical: ##STR59## the residue of the amino acid Sta, AHPPA or ACHPA; X represents the residue of one of the amino acids Ile or Ala; and R₅ represents an aliphatic or cyclic hydrocarbon group of 3 to 20 carbon atoms which is unsubstituted or substituted by a phenyl or hydroxyphenyl group, the said hydrocarbon group simultaneously containing at least one hydroxyl group and at least one carbon atom not having a C--H bond;and also any pharmaceutically acceptable salts of the said peptide amino alcohol with mineral or organic acids or with alkali metals or alkaline earth metals.
 9. A peptide amino-alcohol derivative as claimed in claim 8, in which R₅ represents a group chosen from: ##STR60##
 10. A pharmaceutical composition for inhibition of renin-angiotensin enzyme systems which contains an renin-angiotensin enzyme inhibiting amount, as the active ingredient, of the product as claimed in claim
 1. 11. A pharmaceutical composition which contains, as the active ingredient, from 1 to 1000 mg of a product as claimed in claim 1, per dosage unit, mixed with a pharmaceutical excipient.
 12. A pharmaceutical composition which contains, as the active ingredient, a product as claimed in claim
 8. 13. A pharmaceutical composition which contains, as the active ingredient, from 1 to 1000 mg of a product as claimed in claim 8, per dosage unit, mixed with a pharmaceutical excipient. 